Many plant disease resistance (R) proteins belong to the family of nucleotide-binding-leucine rich repeat (NB-LRR) proteins. NB-LRRs mediate recognition of pathogen-derived effector molecules and subsequently activate host defence. Their multi-domain structure allows these pathogen detectors to simultaneously act as sensor, switch and response factor. Structure–function analyses and the recent elucidation of the 3D structures of subdomains have provided new insight in how these different functions are combined and what the contribution is of the individual subdomains. Besides interdomain contacts, interactions with chaperones, the proteasome and effector baits are required to keep NB-LRRs in a signalling-competent, yet auto-inhibited state. In this review we explore operational models of NB-LRR functioning based on recent advances in understanding their structure.
► The N-terminal CC and TIR domain of Mla1 and L6 form homo dimers that are required and sufficient to induce cell death. ► Steady-state levels of signalling-competent NB-LRR R proteins are co-regulated by chaperones and the proteasome. ► NB-LRR activation is a multistep process requiring fine-tuned intramolecular interactions between co-evolved subdomains. ► 3D modelling of NB-LRR structures aids predicting the conformational changes underlying R protein function and activity. ► Changes in the conformational fold of NB-LRR R proteins correlate with distinct subcellular localisations.